JP2009534406A - Inhibitors of c-fms kinase - Google Patents

Abstract

［式中、Ｚ、Ｘ、Ｊ、Ｒ^２およびＷは本明細書に示す通りである］
で表される化合物ばかりでなくこれらの溶媒和物、水化物、互変異性体および製薬学的に許容される塩に向けたものであり、これらは蛋白質チロシンキナーゼ、特にｃ−ｆｍｓキナーゼを阻害する。また、式（Ｉ）で表される化合物を用いて自己免疫病および炎症性要素を伴う病気を治療、卵巣癌、子宮癌、乳癌、前立腺癌、肺癌、結腸癌、胃癌、ヘアリー細胞白血病からの転移を治療、および腫瘍転移または変形性関節症が原因の骨格痛または内蔵、炎症および神経原性疼痛を包含する痛みばかりでなく骨粗しょう症、パジェット病および病的状態に骨吸収が介在する他の病気（関節リウマチおよび他の形態の炎症性関節炎、変形性関節症、人工器官不全、溶骨性肉腫、骨髄腫および骨への腫瘍転移を包含）を治療する方法も提供する。The present invention relates to a compound of formula (I):
[Chemical 1]

[Wherein Z, X, J, R ² and W are as defined herein]
As well as their solvates, hydrates, tautomers and pharmaceutically acceptable salts, which inhibit protein tyrosine kinases, particularly c-fms kinase. To do. In addition, the compounds of formula (I) are used to treat autoimmune diseases and diseases with inflammatory components, from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia Treat metastases, and bone resorption mediated by osteoporosis, Paget's disease and pathological conditions as well as pain, including skeletal pain or viscera due to tumor metastasis or osteoarthritis, inflammation and neurogenic pain Also provided are methods of treating various diseases of rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthetic dysfunction, osteolytic sarcoma, myeloma and tumor metastasis to bone.

Description

CROSS REFERENCE TO RELATED APPLICATION This application is a priority from US Provisional Application Serial No. 60 / 793,667, filed April 20, 2006, the contents of which are hereby incorporated by reference in their entirety. Is an insistence.

  The present invention relates to novel compounds that function as protein tyrosine kinase inhibitors. More particularly, the present invention relates to novel compounds that function as inhibitors of c-fms kinase.

  Protein kinases are key to the signal transduction pathway by catalyzing the transfer of adenosine 5'-triphosphate (ATP) to the terminal tyrosine, serine and threonine hydroxyl groups of proteins. Is an enzyme that acts as an ingredient. As a result, protein kinase inhibitors and substrates are valuable tools for assessing the physiological consequences of protein kinase activation. It has been demonstrated that over- or inappropriate expression of normal or mutant protein kinases in mammals plays an important role in the development of various diseases including cancer and diabetes.

  Protein kinases can be classified into the following two types: kinases that preferentially phosphorylate tyrosine residues (protein tyrosine kinases) and kinases that preferentially phosphorylate serine and / or threonine residues (protein serine / Threonine kinase). Protein tyrosine kinases perform a variety of functions ranging from stimulating cell proliferation and differentiation to blocking cell proliferation. They can be classified as either receptor protein tyrosine kinases or intracellular protein tyrosine kinases. Receptor protein tyrosine kinases are divided into 20 subfamilies, which have intrinsic tyrosine kinase activity in addition to having an extracellular ligand binding region and an intracellular catalytic region.

  The epidermal growth factor (“EGF”) family of receptor tyrosine kinases, including HER-1, HER-2 / neu and HER-3 receptors, are found in extracellular binding regions, membrane regions and intracellular Contains a cytoplasmic catalytic region. Receptor binding initiates a number of intracellular tyrosine kinase-dependent phosphorylation processes that ultimately result in oncogene transcription. Breast cancer, colorectal cancer and prostate cancer are related to the family of receptors.

  Insulin receptor (“IR”) and insulin-like growth factor I receptor (“IGF-1R”) are structurally and functionally related but exert different biological effects. Overexpression of IGF-1R is associated with breast cancer.

  Platelet derived growth factor ("PDGF") receptors mediate cellular responses including proliferation, migration and survival, including PDGFR, stem cell factor receptor (c-kit) and c-fms. Such receptors have been implicated in diseases such as atherosclerosis, fibrosis and proliferative vitreoretinopathy.

  Fibroblast growth factor (“FGR”) receptors are composed of four types of receptors involved in blood vessel formation, limb growth and the proliferation and differentiation of various types of cells.

Various tumors, including ovarian cancer, produce large amounts of vascular endothelial growth factor (“VEGF”), a potent mitogen for endothelial cells. Known receptors for VEGF are denoted as VEGFR-1 (Flt-1), VEGFR-2 (KDR), and VEGFR-3 (Flt-4). A related group of receptors, tie-1 and tie-2 kinases, have been identified in vascular endothelium and hematopoietic cells. VEGF receptors are involved in angiogenesis and angiogenesis.

  Intracellular protein tyrosine kinases are also known as non-receptor protein tyrosine kinases. More than 24 such kinases have been identified and classified into 11 subfamilies. Serine / threonine protein kinases are mainly present in cells, as are cellular protein tyrosine kinases.

Diabetes, angiogenesis, psoriasis, restenosis, eye disease, schizophrenia, rheumatoid arthritis, cardiovascular disease and cancer are examples of diseases that develop in connection with abnormal protein tyrosine kinase activity. Thus, there is a need for potent selective small protein tyrosine kinase inhibitors that are potent. Patent Documents 1, 2, 3, 4, 5, 6 and 7 show recent attempts to synthesize such inhibitors.
US Pat. No. 6,383,790 US Pat. No. 6,346,625 US Pat. No. 6,235,746 US Pat. No. 6,100,254 PCT International Application WO01 / 47897 PCT International Application WO00 / 27820 PCT International Application WO02 / 068406

SUMMARY OF THE INVENTION The present invention addresses the need for such potent selective protein tyrosine kinase inhibitors that are currently needed by providing potent inhibitors of c-fms kinase. The present invention relates to formula I:

[Where:
W is

And each R ⁴ is independently H, F, Cl, Br, I, OH, OCH ₃ , OCH ₂ CH ₃ , SC _(1-4) alkyl, SOC _(1-4) alkyl, SO ₂ C _(1-4) alkyl, —C _(1-3) alkyl, CO ₂ R ^d , CONR ^e R ^f , C≡CR ^g or CN; and R ^d is H or —C _{(1-3 A)} alkyl;
R ^e is H or —C _(1-3) alkyl;
R ^f is H or —C _(1-3) alkyl; and R ^g is H, —CH ₂ OH or —CH ₂ CH ₂ OH;
R ² is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl, spiro-substituted piperidinyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, all of which are independently: Optionally substituted with one or two of each of fluoro, hydroxy, C _(1-3) alkyl and C _(1-4) alkyl;
Z is H, F or CH ₃ ;
J is CH or N;
X is

Is;
R ⁵ is, _{H, -C (1-6) alkyl, -OC (1-4) ^{alkyl, -CN, -NA 3 A 4,}} -SO 2 CH 3, -CO 2 C (1-4) alkyl, _{^{-CH 2 -NA 3 A 4, -CH}} 2 CH 2 NA 3 A 4, -CONA 3 A 4, -CH 2 OC (1-4) _{alkyl, -OC (1-4)} alkyl ^OR a, -NHCH ₂ CH ₂ CO ₂ C _{(1-4) alkyl, -NHCH 2 CH 2 OC (1-4} ) alkyl, _{-N (C (1-4) ^{alkyl) CH 2 CH 2 NA 3 A}} 4, -OC (1- ₄₎ alkyl _{^{NA 3 A 4, -OCH 2 CO}} 2 C (1-4) _{alkyl, -CH 2 CO 2 C (1-4} ) _{alkyl, -CH 2 CH 2 SO 2 C} (1-4) alkyl, - ^{_{SO 2 CH 2 CH 2 NA 3}} A 4, -SOCH 2 CH 2 _{^{A 3 A 4, -SCH 2 CH}} 2 NA 3 A 4, -NHSO 2 CH 2 CH 2 NA 3 A 4, phenyl, imidazolyl, thiazolyl, 4H-[l, 2,4] oxadiazol-5-onyl, 4H-pyrrolo [2,3-b] pyrazinyl, pyridinyl, [1,3,4] oxadiazolyl, 4H- [1,2,4] triazolyl, tetrazolyl, pyrazolyl, [1,3,5] triazinyl or [1, 3,4] thiadiazolyl;
A ³ is —C _(1-4) alkyl or CH ₂ CH ₂ OR ^a ;
A ⁴ is —C _(1-4) alkyl, COR ^a , CH ₂ CON (CH ₃ ) ₂ , —CH ₂ CH
_{^{2 OR a, -CH 2 CH 2}} SC (1-4) _{alkyl, -CH 2 CH 2 SOC (1-4} ) alkyl or _{-CH 2 CH 2 SO 2 C (} 1-4) or alkyl; or A ³ and ^{a 4} are taken together to form the following:

A nitrogen-containing heterocyclic ring selected from: and R ^a is H or C _(1-4) alkyl;
R ^aa is H or C _(1-4) alkyl; and R ^bb is H, —C _(1-4) alkyl, —CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ , —CH ₂ CO ₂ H _{, -C (O) C (1-4} ) alkyl or _{CH 2 C (O) C (} 1-4) alkyl]
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.

Whenever ^a variable, such as R ^a, appears more than once in the Formula I embodiment throughout this specification and the present application, each such substituent is independently defined. Throughout this specification and throughout this application, the terms “Me”, “Et”, “Pr” and “Bu” refer to methyl, ethyl, propyl and butyl, respectively.

Detailed Description of the Invention The present invention provides compounds of formula I:

[Where:
W is

And each R ⁴ is independently H, F, Cl, Br, I, OH, OCH ₃ , OCH ₂ CH ₃ , SC _(1-4) alkyl, SOC _(1-4) alkyl, SO ₂ C _(1-4) alkyl, —C _(1-3) alkyl, CO ₂ R ^d , CONR ^e R ^f , C≡CR ^g or CN; and R ^d is H or —C _{(1-3 A)} alkyl;
R ^e is H or —C _(1-3) alkyl;
R ^f is H or —C _(1-3) alkyl; and R ^g is H, —CH ₂ OH or —CH ₂ CH ₂ OH;
R ² is cycloalkyl (including cyclohexenyl and cycloheptenyl), spiro-substituted cycloalkenyl (spiro [2.5] oct-5-enyl, spiro [3.5] non-6-enyl, spiro [4.5] Including deco-7-enyl and spiro [5.5] undec-2-enyl), heterocyclyl (including piperidinyl), spiro-substituted piperidinyl (3-aza-spiro [5.5] undecanyl and 8-aza-spiro [ 4.5] decanyl), thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, all of which are independently: chloro, fluoro, hydroxy, C _{(1-3 )} optionally substituted by one or two of each in the alkyl and C _(1-4) alkyl (The substituted cycloalkyl includes 4,4-dimethylcyclohexenyl, 4,4-diethylcyclohexenyl, 4-methylcyclohexenyl, 4-ethylcyclohexenyl, 4-n-propylcyclohexenyl, 4-iso- Propylcyclohexenyl and 4-t-butylcyclohexenyl are included; the substituted piperidinyl includes 4-methylpiperidinyl, 4-ethylpiperidinyl, 4- (1′hydroxyeth-2′yl) piperidinyl And 4,4 dimethylpiperidinyl).
Z is H, F or CH ₃ ;
J is CH or N;
X is

Is;
R ⁵ is, _{H, -C (1-6) alkyl, -OC (1-4) ^{alkyl, -CN, -NA 3 A 4,}} -SO 2 CH 3, -CO 2 C (1-4) alkyl, _{^{-CH 2 -NA 3 A 4, -CH}} 2 CH 2 NA 3 A 4, -CONA 3 A 4, -CH 2 OC (1-4) _{alkyl, -OC (1-4)} alkyl ^OR a, -NHCH ₂ CH ₂ CO ₂ C _{(1-4) alkyl, -NHCH 2 CH 2 OC (1-4} ) alkyl, _{-N (C (1-4) ^{alkyl) CH 2 CH 2 NA 3 A}} 4, -OC (1- ₄₎ alkyl NA ³ A ⁴ , —OCH ₂ CO ₂ C _(1-4) alkyl, —CH
₂ CO ₂ C _{(1-4) alkyl, -CH 2 CH 2 SO 2 C} (1-4) ^{_{alkyl, -SO 2 CH 2 CH 2 NA}} 3 A 4, -SOCH 2 CH 2 NA 3 A 4, -SCH _{^{2 CH 2 NA 3 A 4,}} -NHSO 2 CH 2 CH 2 NA 3 A 4, phenyl, imidazolyl, thiazolyl, 4H-[l, 2,4] oxadiazol-5-onyl, 4H-pyrrolo [2,3 -B] pyrazinyl, pyridinyl, [1,3,4] oxadiazolyl, 4H- [1,2,4] triazolyl, tetrazolyl, pyrazolyl, [1,3,5] triazinyl or [1,3,4] thiadiazolyl ;
A ³ is —C _(1-4) alkyl or CH ₂ CH ₂ OR ^a ;
A ⁴ is —C _(1-4) alkyl, COR ^a , CH ₂ CON (CH ₃ ) ₂ , —CH ₂ CH ₂ OR ^a (including —CH ₂ CH ₂ OCH ₃ ), —CH ₂ CH ₂ SC _(1-4) alkyl _{(including -CH 2 CH 2 SCH 3),} - CH 2 CH 2 SOC (1-4) alkyl _(including -CH ₂ CH ₂ SOCH ₃₎ or _-CH 2 _CH 2 _SO 2 C _(1-4) alkyl (including —CH ₂ CH ₂ SO ₂ CH ₃ ); or A ³ and A ⁴ together are:

A nitrogen-containing heterocyclic ring selected from: and R ^a is H or C _(1-4) alkyl;
R ^aa is H or C _(1-4) alkyl; and R ^bb is H, —C _(1-4) alkyl, —CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ , —CH ₂ CO ₂ H _{, -C (O) C (1-4} ) alkyl or _{CH 2 C (O) C (} 1-4) alkyl]
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.

A preferred embodiment of the present invention is:
W is

Is;
R ² is

Is;
Z is H;
J is CH or N;
X is

Is;
R ⁵ is H, —C _(1-6) alkyl, phenyl, —CH ₂ CH ₂ NA ³ A ⁴ , —CH ₂ CH ₂ SO ₂ CH ₃ , pyridyl, imidazolyl, —CH ₂ NA ³ A ⁴ or —CH ₂ OR ^a ; and A ³ is —CH ₃ ;
A ⁴ is —COCH ₃ or —CH ₃ ; or A ³ and A ⁴ together are:

May form a nitrogen-containing heterocyclic ring selected from:
R ^a is H or —C _(1-4) alkyl;
R ^bb is —C _(1-4) alkyl or —COCH ₃ ;
These are solvates, hydrates, tautomers and pharmaceutically acceptable salts as well as compounds.

Another aspect of the present invention provides:
W is

Is;
R ² is

Is;
Z is H;
J is CH or N;
X is

Is;
R ⁵ is —C _(1-3) alkyl, —CH ₂ NA ³ A ⁴ or —CH ₂ OR ^a ; and A ³ is —CH ₃ ;
A ⁴ is —COCH ₃ or —CH ₃ ; or A ³ and A ⁴ together are:

May form a nitrogen-containing heterocyclic ring selected from:
R ^a is H or —C _(1-4) alkyl;
R ^bb is —C _(1-4) alkyl or —COCH ₃ ;
These are solvates, hydrates, tautomers and pharmaceutically acceptable salts as well as compounds.

Another aspect of the present invention provides:
W is

Is;
R ² is

Is;
Z is H;
J is CH or N;
X is

Is
These are solvates, hydrates, tautomers and pharmaceutically acceptable salts as well as compounds.

Another aspect of the present invention provides:
W is

Is;
R ² is

Is;
Z is H;
J is CH or N;
X is

Is
These are solvates, hydrates, tautomers and pharmaceutically acceptable salts as well as compounds.

Another aspect of the present invention provides:
W is

Is;
R ² is

Is;
Z is H;
J is CH or N;
X is

Is;
R ⁵ is —C _(1-3) alkyl, —CH ₂ NA ³ A ⁴ or —CH ₂ OR ^a ; and A ³ is —CH ₃ ;
A ⁴ is —COCH ₃ or —CH ₃ ; or A ³ and A ⁴ together are:

May form a nitrogen-containing heterocyclic ring selected from:
R ^a is H or —C _(1-4) alkyl;
R ^bb is —C _(1-4) alkyl or —COCH ₃ ;
These are solvates, hydrates, tautomers and pharmaceutically acceptable salts as well as compounds.

  Another aspect of the invention is composed of Example Nos. 1, 2, 3, 4, 5 and their solvates, hydrates, tautomers and pharmaceutically acceptable salts and any combination thereof. .

  The present invention also relates to a method of inhibiting protein tyrosine kinase activity by administering to a mammal at least one compound of formula I in a therapeutically effective amount. A preferred tyrosine kinase is c-fms.

  The present invention is intended to encompass not only enantiomeric, diastereomeric and tautomeric forms of all compounds of formula I, but also their racemic mixtures. In addition, some of the compounds of Formula I can be prodrugs, ie, agonist derivatives that have superior delivery capabilities and therapeutic value compared to the agonist. Prodrugs are transformed into active drugs by in vivo enzymes or chemical processes.

I. DEFINITIONS The term “alkyl” refers to both straight and branched groups having no more than 12 carbon atoms, preferably no more than 6 carbon atoms, unless otherwise specified, and is not limited thereto. Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl Is included.

  The term “cycloalkyl” refers to a saturated or partially unsaturated ring having from 3 to 8 carbon atoms. There may optionally be 4 or fewer alkyl substituents in the ring. Examples include cyclopropyl, 1,1-dimethylcyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and 4,4-dimethylcyclohexenyl.

  The term “alkylamino” refers to an amino having one alkyl substituent and the amino group being the point of attachment to the rest of the molecule.

  The term “alkoxy” refers to a straight or branched group having 12 or fewer carbon atoms, unless otherwise specified, attached to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.

  The term “spiro-substituted cycloalkenyl” refers to a pair of cycloalkyl rings that share one carbon atom and at least one of the rings is partially unsaturated, for example:

And so on.

  The term “spiro-substituted heterocyclyl” refers to a heterocyclyl and cycloalkyl ring sharing one carbon atom, for example:

And so on.

II. Therapeutic uses The compounds of formula I correspond to novel potent inhibitors such as protein tyrosine kinases such as c-fms and are used for the prevention and treatment of diseases caused by the action of such kinases. Can be useful.

  The present invention also provides a method of inhibiting protein tyrosine kinase, comprising contacting said protein tyrosine kinase with an effective inhibitory amount of at least one of the compounds of formula I. Become. A preferred tyrosine kinase is c-fms. The compounds of the present invention are also inhibitors of FLT3 tyrosine kinase activity. In one embodiment of inhibiting protein tyrosine kinases, at least one of the compounds of formula I is combined with a known tyrosine kinase inhibitor.

  In various embodiments of the invention, the protein tyrosine kinase that is inhibited by the compound represented by Formula I is present in a cell, in a mammal, or in vitro. For mammals (including humans), at least one pharmaceutically acceptable form of the compound of Formula I is administered in a therapeutically effective amount.

  The present invention further provides a method of treating cancer in mammals, including humans, which treats a pharmaceutically acceptable composition of at least one compound of formula I. By administering in an effective amount. Typical cancers include, but are not limited to, acute myeloid leukemia, acute lymphocytic leukemia, ovarian cancer, uterine cancer, prostate cancer, lung cancer, breast cancer, colon cancer, gastric cancer and hairy cell leukemia. The present invention also provides a method of treating certain precancerous lesions, including myelofibrosis. In one aspect of the invention, at least one compound of formula I is administered in an effective amount in combination with an effective amount of a chemotherapeutic agent.

  The present invention further includes methods for treating and preventing metastasis caused by cancer including, but not limited to, ovarian cancer, uterine cancer, prostate cancer, lung cancer, breast cancer, colon cancer, gastric cancer and hairy cell leukemia. provide.

The present invention further includes osteoporosis, Paget's disease and other diseases in which bone resorption is mediated by pathological conditions [rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthetic dysfunction, osteolytic sarcoma. , Including myeloma and tumor metastasis to bone, including but not limited to, often occurring in the case of cancers including breast cancer, prostate cancer, and colon cancer].

  The present invention also provides a method for treating pain, particularly visceral, inflammation and neurogenic pain as well as skeletal pain caused by tumor metastasis or osteoarthritis.

  The present invention also provides a method of treating cardiovascular, inflammatory and autoimmune diseases in mammals, including humans, which comprises at least one pharmaceutical agent of the compounds of formula I. A method by administering a pharmaceutically acceptable form in a therapeutically effective amount. Examples of diseases with inflammatory components include glomerulonephritis, inflammatory bowel disease, artificial organ failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes, Tumor-related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia or Alzheimer's dementia. They can be effectively treated with the compounds of the present invention. Other diseases that can be effectively treated include, but are not limited to, atherosclerosis and cardiac hypertrophy.

  Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis or uveitis can also be treated with the compounds of the present invention.

  As used herein, the term “therapeutically effective amount” means that the active compound or drug being sought by a researcher, veterinarian, doctor or other clinician is biological or pharmaceutical in a tissue system, animal or human. Means an amount that elicits a general response, including reduction, prevention, treatment or delay in the onset or progression of the disease or disorder to be treated

  When a compound of the invention is used as a protein tyrosine kinase inhibitor, it may be administered once or divided daily in an effective amount within a dosage range of about 0.5 mg to about 10 g, preferably about 0.5 mg to about 5 g. It may be administered. The dosage will be influenced by factors such as route of administration, beneficiary health, weight and age, frequency of treatment and the presence of concurrent and unrelated treatments.

  It will also be apparent to those skilled in the art that the therapeutically effective amount of a compound of the invention or pharmaceutical composition thereof will vary depending on the desired effect. Thus, one skilled in the art can easily determine the optimal dosage to be administered, and the optimal dosage will depend on the particular compound used, the mode of administration, the concentration of the formulation and the progression of the disease state. Will change. In addition, it is necessary to adjust the dosage to an appropriate therapeutic level as a result of factors associated with the individual subject being treated, such as subject age, weight, diet and administration. Time is included. Thus, the dosages given above are typical of the average case. There can, of course, be individual cases where higher or lower dosage ranges are merited, and such are within the scope of this invention.

  The compound represented by the formula I can be constructed into a pharmaceutical composition containing any of the known pharmaceutically acceptable carriers. Typical carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial agent, antibacterial / fungal agent, and isotonic agent. Typical excipients that can be components of the formulation also include fillers, binders, disintegrants and lubricants.

Pharmaceutically acceptable salts of the compounds of formula I include the usual non-toxic salts or quaternary ammonium salts derived from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphoric acid, dodecyl sulfate, hydrochloride, hydrobromide, lactate, This includes maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, and amino acids such as arginine Of salt. It is also possible to subject the basic nitrogen-containing group to quaternization using, for example, an alkyl halide.

  The pharmaceutical composition of the present invention may be administered by any means that achieves its intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. It is also possible to administer by the oral route alternately or simultaneously. Formulations suitable for parenteral administration include aqueous solutions of the active compound, such as aqueous solutions containing water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusions. Complexes are included.

  The present invention also encompasses a method of making a pharmaceutical composition, the method comprising mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. In addition, the present invention also encompasses a pharmaceutical composition made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. As used herein, the term “composition” includes not only a product comprising a specified amount of a specified material, but also any product that results directly or indirectly as a result of combining the specified material in a specified amount. Intended to be included.

Polymorphs and solvates Furthermore, the compounds of the present invention may also take one or more polymorphic or amorphous forms and thus are intended to be included within the scope of the present invention. In addition, the present compounds may form solvates, for example solvates with water (ie hydrates) or solvates with common organic solvents. The term “solvate” as used herein means a physical association of a compound of this invention with one or more solvent molecules. Such physical bonds involve varying degrees of ionic and covalent bonding (including hydrogen bonding). In some cases, such solvates can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term “solvate” is intended to include both solution phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate and the like.

The present invention is intended to include within its scope solvates of the compounds of the present invention. Accordingly, the term “administration” in the methods of treatment of the present invention includes the compounds of the present invention or their solvates not specifically disclosed, but which would clearly be included within the scope of the present invention. Includes means for treating, ameliorating or preventing a syndrome, disease or condition described in the specification.
Preparation method

In Scheme 1, a compound of formula I wherein R ^b is X, a useful intermediate for use in the scheme shown below (where X is available as a starting material or as shown in the scheme shown below). Illustrate general methods suitable for producing compounds of formula 1-6 wherein ^Rb is a leaving group (preferably bromo, chloro or fluoro). For purposes of illustrating the method of this scheme, reactants and conditions are defined for compounds where J is CH. One skilled in the art will appreciate that when J is N, the reaction conditions may be slightly modified and suitable reactants may be required.

Amines of formula 1-1 can be commercially available or can be reduced to nitro compounds of formula 1-0 by standard synthetic methods (Reductions in Organic Chemistry, M. Hudricky, Wiley, New York, see 1984). Suitable conditions are those in which catalytic hydrogenation using a palladium catalyst is carried out in a suitable solvent such as methanol or ethanol. If R ^b is halogen and is not available as an amine of formula 1-1, the reduction of nitro is carried out with iron or zinc in a suitable solvent such as acetic acid or You may carry out in ethanol and water using iron and ammonium chloride.

The compound represented by Formula 1-2, wherein R ² is cycloalkyl, is converted into an intermediate halo compound after ortho-halogenation, preferably bromination, to the amino compound represented by Formula 1-1. Boronic acid or boronic acid ester (Suzuki reaction, when R ² M is R ² B (OH) ₂ or boronic acid ester, N. Miyaura and A. Suzuki, Chem. Rev., 95: 2457 (1995); See Suzuki, Metal-Catalyzed Coupling Reactions, F. Deiderich, P. Stang, Wiley-VCH, Weinheim (1988)) or tin reactant (Still reaction, when R ² M is R ² Sn (alkyl) ₃ JK Still, Angew.Chem, Int.Ed.En gl., 25: 508-524 (1986)). When R ^b is Br, iodo may be introduced such that it reacts preferentially over bromine during the metal catalyzed coupling reaction (compounds where J is CH are commercially available). Is possible). Conditions suitable for bromination of 1-1 are those using N-bromosuccinimide (NBS) in a suitable solvent such as N, N-dimethylformamide (DMF), dichloromethane (DCM) or acetonitrile. . Metal-catalyzed coupling, preferably the Suzuki reaction, is preferably carried out according to standard methods, preferably a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ), an aqueous base such as Na ₂ It can be carried out in the presence of an aqueous CO ₃ solution and a suitable solvent such as toluene, ethanol, 1,4-dioxane, dimethoxyethane (DME) or DMF.

The compound represented by Formula 1-2, wherein R ² is cycloalkylamino (for example, piperidino), is a leaving group L ¹ (preferably a compound represented by Formula 1-3 activated by a nitro group). Is fluoro or chloro) in the presence of a suitable base such as K ₂ CO ₃ , N, N-diisopropylethylamine (DIEA) or NEt ₃ for nucleophilic aromatic substitution with cycloalkylamine (R ² H; eg piperidine). It can be obtained by forming compound 1-4 by receiving and then reducing the nitro group as described above.

Next, an amino group and a heterocyclic acid P ¹ -WCOOH (or a corresponding salt P ¹ -WCOOM ² thereof, where M ² is Li, Na, or K included in the compound represented by Formula 1-2 [Wherein P ¹ is any protecting group such as 2- (trimethylsilyl) ethoxymethyl (SEM) when W is, for example, imidazole, triazole, pyrrole or benzimidazole], or P 1 ¹ may not be present when W is, for example, furan etc.] (for the list of protecting groups for W Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic) Synthesis, John Wiley and Sons, Inc., NY (1991). Irradiation). The coupling is in accordance with standard procedures suitable for amide bond formation (see below for review: M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NY (1984)) or acid chloride. In reaction with P ¹ -WCOCl or active ester P ¹ -WCO ₂ R ^q, where R ^q is a leaving group such as pentafluorophenyl or N-succinimide, etc. The compounds represented can be produced. Suitable reaction conditions for coupling with P ¹ -WCOOH or P ¹ -WCOOM ² are oxalyl chloride as catalyst in dichloromethane (DCM) when W is furan (no optional protecting group P ¹ is present). Conditions that cause the coupling in the presence of a trialkylamine such as N, N-diisopropylethylamine (DIEA) after use with DMF to give the acid chloride WCOCl; W is pyrrole (optional protecting group P ¹ is absent) conditions using 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt) hydrochloride; and W is imidazole, pyrrole or benzimidazole (optional suitable conditions for the the presence of P ¹⁾ of The solvent Kisafuruoro phosphate bromo tripyrrolidinophosphonium (PyBroP) and DIEA, for example, a condition of using a medium such as DCM or DMF.

When an arbitrary protecting group P ¹ as described above is contained in W in the compound represented by the formula 1-5, the compound represented by the formula 1-6 is produced by removing it at that time. Can be made. For example, when W is an imidazole in which nitrogen is protected with a SEM group, removal of the SEM group can be accomplished by acidic reactants such as trifluoroacetic acid (TFA) or fluoride sources such as tetrabutylammonium fluoride (TBAF). (See Green and Wuts above).

Finally, it is understood that compounds of formula I (ie, formula 1-6 where R ^b is X) may be further derivatized. Examples of further derivatization include, but are not limited to: If the compound of formula I contains a cyano group, hydrolysis of the group under acidic or basic conditions In the case where the compound represented by formula I contains an ester, the ester is hydrolyzed to form an acid, and the acid is converted to an amide bond. It may be converted to an amide in the manner described above for formation. Amides may be converted to amines in the Curtius or Schmidt reaction (for review see Angew. Chemie Int. Ed., 44 (33), 5188-5240, (2005)) or reduction of the cyano group. It is also possible to obtain amines by receiving (Synthesis, 12, 995-6, (1988) and Chem. Pharm. Bull., 38 (8), 2097-101, (1990)). An acid can be reduced to give an alcohol, and an alcohol can be oxidized to give an aldehyde and a ketone. Conditions suitable for subjecting the carboxylic acid to reduction in the presence of a cyano group include conditions using sodium borohydride and ethyl chloroformate in tetrahydrofuran (THF); and oxidation of the alcohol to Dess-Martin peadinane. (Periodinane) reactant may be used (Adv. Syn. Catalysis 346, 111-124 (2004)). Reacting aldehydes and ketones with primary or secondary amines in the presence of a reducing agent such as sodium triacetoxyborohydride (see J. Org. Chem., 61, 3849-3862, (1996)). The amine can be obtained by reductive amination with Olefin can be reduced by catalytic hydrogenation. When the compound of formula I contains an acyclic or cyclic sulfide, the sulfide can be further oxidized to give the corresponding sulfoxide or sulfone. The sulfoxide can be oxidized by oxidation with a suitable oxidizing agent such as 1 equivalent of meta-chloroperbenzoic acid (MCPBA) or treated with NaIO ₄ (eg J. Med. Chem., 46: 4676- 86 (see 2003)) and the sulfone is treated with 2 equivalents of MCPBA or with 4-methylmorpholine N-oxide and a catalytic amount of osmium tetroxide (eg, PCT application). WO 01/47919). It is also possible to prepare both sulfoxide and sulfone by using 1 equivalent and 2 equivalents of H ₂ O ₂ respectively in the presence of titanium (IV) isopropoxide (see, for example, J. Chem. Soc. Perkin Trans. 2, 1039-1051 (2002)).

  In Scheme 2, X is

And G is O (where n is 1-2) or NR ^a (where n is 1), illustrating the synthesis of compounds of formula I.

For purposes of illustrating the synthetic strategy in this scheme, reactants and conditions are defined for substrates where J is CH. It is understood that a similar synthesis method can be used with some modifications when J is N.

The starting compound 1-5 ( ^Rb is Br) is obtained as described in Scheme 1. If any protecting group P ¹ is present, its removal may be carried out as described in Scheme 1 at that time to give compound 1-6, which is also the starting point in this synthetic procedure. It can be used as a material.

Bromide 1-5 to alkoxyvinyltin reactant (where R ⁶ is H, C _1-5 alkyl, OC _(1-4) alkyl, NA ³ A ⁴ , CH ₂ NA ³ A ⁴ , CO ₂ C _{(1 -4)} alkyl, CH ₂ SO ₂ C, which is _(1-4) alkyl) was shown to be still coupled (see for example J. Org. Chem., 48: 1559-60 (1983)). Thus, compound 2-1 can be produced. A ketone is obtained by subjecting the vinyl alkyl ether group (C _(1-4) alkyl OC═CH (R ⁶ ) —) in compound 2-1 to hydrolysis using an acidic reactant such as trifluoroacetic acid or acetic acid. 2-2 can be produced (in this case, = CH-R ⁶ becomes -R ⁵ ). If any protecting group P ¹ is stable to the hydrolysis conditions, its removal may also occur at that time to give 2-4 as described in Scheme 1.

Alternatively, the reaction of 1-6 with an organolithium intermediate (such as occurs for the purpose of converting 1-6 to yield 4-1 as shown in Scheme 4) is performed with an appropriate electrophile R ⁵ COL ³ For example, acid chloride (L ^{3 in} this case is Cl; see eg J. Med. Chem., 48, 3930-34 (2005)) or Weinreb amide (in this case L ³ is N (OMe) Me 2-4 can also be obtained directly by waving using, for example, Bioorg.Med.Chem.Lett., 14 (2): 455-8 (2004)).

Ketone 2-4 is a 5- or 6-membered ring ketal of formula I wherein G is O and n is 1-2 (Protective Groups in Organic Synthesis, TH Greene and Peter GM Wuts, John Wiley and Sons, NY (1991)) or a 5-membered ring aminal of formula I (Bergmann, ED, Chem. Rev. G) wherein G is NR ^a and n is 1. 309-352 (1953) and Gosain, R. et al., Tetrahedron Lett., 40, 6673-6 (1999)). The synthesis of the 5-membered or 6-membered ring ketal (G is O) is synthesized by 1,2-ethanediol (where n is 1) or 1,3-propanediol (where n is 2). And a suitable acid catalyst, preferably para-toluenesulfonic acid or the like, is used in an anhydrous solvent, preferably benzene or toluene.

Similarly, compound 2-2, which may optionally be protected when P ¹ is selected to be stable to ketal and aminal formation conditions, is also immediately described above as described above for ketal or aminal 2 Can be converted to -3, and then subjected to deprotection as described in Scheme 1 to give compounds of formula I.

  It is understood that further derivatization of the functional groups of the compounds shown in this scheme can be accomplished as outlined in Scheme 1.

Scheme 3 gives the 2-imidazole carboxylate of formula 3-5, wherein R ^a is H or C _(1-4) alkyl and R ^d is H, alkyl, —CN or —CONH ₂ . Illustrated is the route, which is used as an intermediate in the synthesis of compounds of formula I where W is imidazole.

Is the imidazole represented by formula 3-1 wherein R ^a is H or C _(1-4) alkyl and R ^c is H, C _(1-4) alkyl or —CN, commercially available? Alternatively, when R ^c is —CN, dehydration may be carried out after reacting hydroxylamine with a commercially available aldehyde (3-1 where R ^c is CHO), such as phosphorus oxychloride or anhydrous It can be easily obtained by using acetic acid or the like (Synthesis, 677, 2003). Protecting the imidazole represented by formula 3-1 with a suitable group (P ¹ ), such as methoxymethylamine (MOM) or preferably SEM group, yields a compound represented by formula 3-2. (See Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., NY (1991)).

Halogenation of the imidazole represented by formula 3-2 wherein R ^c is —CN, using a suitable reactant such as N-bromosuccinimide or N-iodosuccinimide, a solvent under electrophilic conditions, L ⁸ for example in DCM or CH ₃ CN or in a solvent such as CCl ₄ under radical conditions in the presence of an initiator such as azobis (isobutyronitrile) (AIBN). Gives a compound of formula 3-3 in which is a leaving group (preferably bromo or iodo). The compound represented by Formula 3-3 is subjected to halogen-magnesium exchange to form an organomagnesium species, and then reacted with an appropriate electrophile to yield the compound represented by Formula 3-4. Let Suitable conditions for the halogen-magnesium exchange are those in which an alkyl-magnesium reactant, preferably isopropylmagnesium chloride, is used in a suitable solvent such as THF at a temperature of -78 ° C to 0 ° C. A suitable electrophile is ethyl chloroformate or ethyl cyanoformate. For an example of subjecting cyanoimidazole to halogen-magnesium exchange, see J. Am. Org. Chem. 65, 4618, (2000).

In the case of the imidazole represented by formula 3-2 where R ^c is not —CN, it is deprotonated with a suitable base, such as alkyl lithium, and then it is subjected to electrophilic agent and organomagnesium species thereon. Can be directly converted to the imidazole of formula 3-4 by reacting as described for. Suitable conditions are those in which the reaction of the resulting organolithium species is quenched with ethyl chloroformate after the imidazole is treated with n-butyllithium in -78 ° C. in THF (eg, Tetrahedron Lett., 29, 3411-3414, (1988)).

Next, the ester represented by the above formula 3-4 is hydrolyzed to give the carboxylic acid represented by the formula 3-5 (M is H) or the carboxylate (M is Li, Na or K). Decomposition can be effected in a suitable solvent such as ethanol or methanol using 1 equivalent of an aqueous metal hydroxide (MOH) solution, preferably an aqueous potassium hydroxide solution. For the synthesis of the compound represented by formula 3-5 in which R ^d is —CONH ₂ , an appropriate alkoxide such as potassium ethoxide is first used for the compound represented by formula 3-4 in which R ^c is —CN. The cyano group is changed to an imidate group by the treatment (Pinner reaction), and then both the ester and the imidate group are hydrolyzed using 2 equivalents of a metal hydroxide aqueous solution.

Scheme 4 illustrates a route to give 2-imidazole carboxylates of formula 4-3 or 4-5 where R ^e is chloro or bromo and M is H, Li, K or Na, It is used as an intermediate when synthesizing a compound of formula I where W is imidazole.

  Preparation of the compound of formula 4-1 is carried out by first protecting the commercially available ethyl imidazole carboxylate according to the method outlined in Scheme 8 and preferably using the SEM group. .

Preparation of a compound of formula 4-2 and a compound of formula 4-1 and 1 equivalent of a suitable halogenating agent such as NBS or NCS, etc. at 25 ° C. in a suitable solvent such as CH ₃ CN, DCM Alternatively, the reaction is performed in DMF or the like. Preparation of a compound of formula 4-4 and a compound of formula 4-1 and 2 equivalents of a suitable halogenating agent such as NBS or NCS in a suitable solvent such as CH ₃ CN or DMF The reaction is carried out at a temperature in the range of 30 ° C to 80 ° C. The imidazoles of formulas 4-3 and 4-5 are then obtained by subjecting the individual esters to hydrolysis as described in Scheme 3.

Scheme 5 illustrates a method for producing an imidazole of formula 5-3, wherein R ^f is —SCH ₃ , —SOCH ₃ or —SO ₂ CH ₃ and M is H, Li, K or Na. Is used as an intermediate in the synthesis of compounds of formula I where W is imidazole.

Imidazole 5-1 (WO1996011932) is protected according to the method described in Scheme 3 and preferably using a SEM protecting group to give the compound of formula 5-2. Hydrolysis of the ester according to the procedure shown in Scheme 3 yields a compound of formula 5-3 where R ^f is —SCH ₃ . ^Rf is —SOCH by subjecting 2-methylthioimidazole of the formula 5-2 to oxidation with 1 equivalent of an appropriate oxidizing agent followed by hydrolysis of the ester according to the procedure shown in Scheme 3. To give the compound of formula 5-3 which is ₃ . Compound represented by formula 5-3, wherein R ^f is —SO ₂ CH ₃ by performing ester hydrolysis according to the procedure shown in Scheme 3 after performing oxidation with 2 equivalents of an appropriate oxidizing agent Give rise to A suitable reactant for this oxidation is MCPBA in DCM. See Scheme 1 for the conversion of sulfides to sulfoxides and sulfones.

  The following examples are for illustrative purposes only and are in no way meant to limit the invention.

5-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxolan-2-yl) -phenyl] -amide

a) 1- (2-Trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile

The flask was charged with imidazole-4-carbonitrile (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K _2. CO ₃ (1.40 g, 10.4 mmol) and acetone (5 mL) were charged and stirred at room temperature for 10 hours. The mixture was diluted with EtOAc (20 mL), washed with water (20 mL) and brine (20 mL), and the organic layer was dried over MgSO ₄ . The crude product was eluted from a 20-g solid phase extraction (SPE) cartridge (silica) with 30% EtOAc / hexanes to give 0.80 g (70%) of the title compound as a colorless oil. Mass spectrum (CI (CH ₄ ), m / z): Calculated as follows: C ₁₀ H ₁₇ N ₃ OSi, 224.1 (M + H), measured value: 224.1.

b) 2-Bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile

1- (2-Trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile (0.70 g, 3.1 mmol) (as prepared at the stage indicated above) was added to CCl ₄ (10 mL). N-bromosuccinimide (NBS) (0.61 g, 3.4 mmol) and azobis (isobutyronitrile) (AIBN) (catalytic amount) were added to the resulting solution, and the mixture was Heated to 60 ° C. for 4 hours. The reaction was diluted with EtOAc (30 mL), washed with NaHCO ₃ (2 × 30 mL) and brine (30 mL), the organic layer was dried over Na ₂ SO ₄ and concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc / hexanes to give 0.73 g (77%) of a yellow solid. Mass spectrum (CI (CH ₄ ), m / z): Value calculated as: C ₁₀ H ₁₆ BrN ₃ OSi, 302.0 / 304.0 (M + H), measured value: 302.1 / 304.1.

c) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester

2-Bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile (0.55 g, 1.8 mmol) (as prepared above) was added to tetrahydrofuran (as prepared above). 2M i-PrMgCl solution in THF (1 mL) was added dropwise to a solution at −40 ° C. that was generated by placing in (THF) (6 mL). The reaction was stirred at −40 ° C. for 10 minutes, then cooled to −78 ° C. and ethyl cyanoformate (0.30 g, 3.0 mmol) was added. The reaction was brought to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous NH ₄ Cl, diluted with EtOAc (20 mL) and then washed with brine (2 × 20 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc / hexanes to give 0.40 g (74%) of a colorless oil. Mass spectrum (ESI, m / z): Calculated as follows: C ₁₃ H ₂₁ N ₃ O ₃ Si, 296.1 (M + H), measured value: 296.1.

d) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid potassium salt

4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester (0.40 g, 1.3 mmol) (as prepared above) To the resulting solution in ethanol (3 mL) was added 6 M KOH solution (0.2 mL, 1.2 mmol) and the reaction was stirred for 10 minutes and then concentrated to 0.40 g (100% ) Of the title compound as a yellow solid. ¹ H-NMR (CD ₃ OD; 400 MHz) δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.8. 00 (s, 9H). Mass spectrum (ESI-neg, m / z): Value calculated as follows: C ₁₁ H ₁₆ KN ₃ O ₃ Si, 266.1 (M−K), measured value: 266.0.

e) 4-Bromo-2-cyclohex-1-enyl-phenylamine

4-Bromo-2-iodo-phenylamine (2.00 g, 6.71 mmol), 2-cyclohex-1-enyl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (1 .40 g, 6.71 mmol) and Pd (PPh ₃ ) ₄ (388 mg, 0.336 mmol) in 40 mL of 1,4-dioxane was added to a 2.0 M Na ₂ CO ₃ aqueous solution ( 26.8 mL, 53.7 mmol) was added. Stirring was performed at 80 ° C. for 5 hours under Ar, and then the reaction was cooled to room temperature. The mixture was treated with EtOAc (100 mL) and washed with H ₂ O (3 × 30 mL) and brine (20 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (10-20% EtOAc / hexanes) to give 1.47 g (87%) of the title compound as a light brown oil. Mass spectrum (ESI, m / z): Calculated as follows: C ₁₂ H ₁₄ BrN, 252.0 (M + H), measured value: 252.0.

f) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl) -amide

4-Bromo-2-cyclohex-1-enyl-phenylamine (1.23 g, 4.88 mmol, as prepared above), 4-cyano-1- (2-trimethylsilanyl-ethoxy Methyl) -1H-imidazole-2-carboxylate (as prepared in step (d) of Example 1 1.49 g, 4.88 mmol) and PyBroP (2.27 g, 4.88 mmol) in 25 mL To the resulting mixture in DMF was added N, N-diisopropylethylamine (DIEA) (2.55 mL, 14.6 mmol). After stirring at room temperature for 16 hours, the mixture was treated with 100 mL EtOAc, washed with H ₂ O (2 × 30 mL) and brine (30 mL), then dried (Na ₂ SO ₄ ). After evaporation of the organic solvent, the residue was purified by flash chromatography on silica gel (5-10% EtOAc / hexanes) to give 2.21 g (90%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ; 400 MHz): δ 9.70 (s, 1H), 8.26 (d, 1H, J = 8.6 Hz), 7.78 (s, 1H), 7.36 (dd 1H, J = 8.6, 2.3 Hz), 7.31 (d, 1H, J = 2.3 Hz), 5.94 (s, 2H), 5.86 (m, 1H), 3.66 (T, 2H, J = 8.3 Hz), 2.19-2.33 (m, 4H), 1.75-1.88 (m, 4H), 0.97 (t, 2H, J = 8. 3 Hz), 0.00 (s, 9H).

g) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl) -amide

4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl) -amide (as indicated above) As prepared, 100 mg, 0.199 mmol), tributyl (1-ethoxyvinyl) stannane (86.3 mg, 0.239 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (10.5 mg, 0.0149 mmol). The resulting mixture in 2 mL of 1,4-dioxane was stirred at 90 ° C. for 2 hours under Ar. The reaction after cooling to room temperature was treated with EtOAc (40 mL) and then washed with 15% aqueous citric acid (2 × 10 mL), H ₂ O (10 mL) and brine (10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (10-20% EtOAc / hexanes) to give 80.1 mg (86%) of the title compound as a light brown oil. Mass spectrum (ESI, m / z): _{Calcd.: C 25 H 32 N 4 O} 3 Si, 465.2 (M + H), Found: 465.1.

h) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxolane- 2-yl) -phenyl] -amide

4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl) -amide (at the steps indicated above) As-prepared, a solution formed by adding 135 mg, 0.290 mmol), ethanediol (363 mg, 5.80 mmol) and a catalytic amount of p-toluenesulfonic acid (PTSA) in 21 mL of benzene was the Dean-Stark. Heated to reflux under conditions for 4 hours. The reaction was diluted with EtOAc (25 mL), washed with water (3 × 20 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH—CHCl ₃ ) to give 100 mg (68%) of the title compound as a white solid. Mass spectrum (ESI, m / z): Calculated as follows: C ₂₇ H ₃₆ N ₄ O ₄ Si, 509.2 (M + H), measured value: 509.0.

i) 5-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxolan-2-yl) -phenyl] -amide 4-cyano- 1- (2-Trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxolan-2-yl) -phenyl ] -Amide (45 mg, 0.088 mmol as prepared above) in 3 mL of THF was added to a solution of tetrabutylammonium fluoride (TBAF) (69 mg, 0.264 mmol). ) Was added. The reaction was stirred at room temperature for 14 hours, at which point the temperature was raised to 60 ° C. over 15 minutes, then diluted with EtOAc (25 mL) and washed with water (3 × 25 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under vacuum. The residue was purified by preparative TLC (10% MeOH—CHCl ₃ ) to give 31 mg (93%) of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ; 400 MHz): δ 9.76 (s, 1H), 8.28 (s, 1H), 7.97 (d, 1H, J = 8.3 Hz), 7.33 (dd 1H, J = 8.3, 2.0 Hz), 7.21 (s, 1H, J = 2.0 Hz), 5.77 (s, 1H), 3.98 (m, 2H), 3.72 (M, 2H), 2.20-2.15 (m, 4H), 1.75-1.66 (m, 4H), 1.56 (s, 3H). Mass spectrum (ESI, m / z): Calculated as follows: C ₂₁ H ₂₂ N ₄ O ₃ , 379.1 (M + H), measured value: 379.1.

4-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxan-2-yl) -phenyl] -amide

a) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxane- 2-yl) -phenyl] -amide

The title compound was prepared from 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl) -amide (implemented). As prepared in step (h) of Example 1 using 0.58 mmol), 1,3-propanediol (882 mg, 11.6 mmol) and a catalytic amount of PTSA as prepared in step (h) of Example 1. (147 mg, 49%). Mass spectrum (ESI, m / z): Calculated as follows: C ₂₈ H ₃₈ N ₄ O ₄ Si, 523.2 (M + H), measured value: 523.3.

b) 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxan-2-yl) -phenyl] -amide of the title compound The preparation was prepared from 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-methyl- [1,3] dioxane- 2-yl) -phenyl] -amide (145 mg, 0.276 mmol as prepared in the above step) and tetrabutylammonium fluoride (216 mg, 0.820 mmol) and the steps of Example 1. Performed by following the procedure shown in (i) (69.4 mg, 64%). ¹ H-NMR (CDCl ₃ ; 400 MHz): δ 9.61 (s, 1H), 8.36 (d, 1H, J = 8.4 Hz), 7.74 (s, 1H), 7.38 (dd 1H, J = 8.4, 1.9 Hz), 7.26 (m, 1H), 5.88 (s, 1H), 3.92-3.79 (m, 4H), 2.34-2 .26 (m, 4H), 2.13 (m, 1H), 1.87-1.77 (m, 4H), 1.52 (s, 3H), 1.28 (m, 1H). Mass spectrum (ESI, m / z): Calculated as follows: C ₂₂ H ₂₄ N ₄ O ₃ , 393.1 (M + H), measured value: 393.1.

4-cyano-1H-imidazole-2-carboxylic acid [2- (4,4-dimethyl-cyclohex-1-enyl) -6- (2-methyl-oxazolidin-2-yl) -pyridin-3-yl]- Amide

a) 6-Bromo-2-iodo-pyridin-3-ylamine

Stir the resulting solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag ₂ SO ₄ (18.1 g, 0.0580 mol) in EtOH (150 mL). To this was added I ₂ (7.59 g, 0.0580 mol) and the reaction was stirred overnight. At that time hexane (200 mL) was added and the resulting mixture was filtered through celite. The solvent was removed in vacuo, dissolved in CHCl ₃ (200 mL), washed with saturated aqueous Na ₂ S ₂ O ₃ (100 mL) and water (1 × 100 mL), then dried (Na ₂ SO ₄ ). After the solvent was concentrated in vacuo, the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexane (100 mL). Filtration yielded 11.2 g (65%) of 6-bromo-2-iodo-pyridin-3-ylamine as a white crystalline material. ¹ H-NMR (CDCl ₃ ; 400 MHz): δ 7.10 (d, 1H, J = 8.2 Hz), 6.74 (d, 1H, J = 8.2 Hz), 4.06 (br s, 2H) ).

b) 6-Bromo-2- (4,4-dimethyl-cyclohex-1-enyl) -pyridin-3-ylamine

6-Bromo-2-iodo-pyridin-3-ylamine (1.00 g, 3.35 mmol, as prepared above) was placed in toluene (27 mL) and EtOH (13.5 mL). The resulting solution was treated with 2.0 M aqueous Na ₂ CO ₃ (13.4 mL, 26.8 mmol) and 4,4-dimethyl-cyclohex-1-enylboronic acid (567 mg, 3.68 mmol). The mixture was degassed by sonication, placed under Ar, treated with Pd (PPh ₃ ) ₄ (271 mg, 0.234 mmol) and then heated to 80 ° C. for 5 hours. The mixture was cooled and diluted with EtOAc (100 mL) and washed with water (2 × 50 mL). The aqueous layers were combined and extracted with EtOAc (1 × 100 mL). The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on a silica gel using a Varian MegaBond Elut 50-g column with 10% EtOAc-hexane to give 668 mg (71%) of 6-bromo-2- (4,4-dimethyl-cyclohex-1-enyl). -Pyridin-3-ylamine was obtained as a tan solid. ¹ H-NMR (CDCl ₃ ; 400 MHz): δ 7.06 (d, 1H, J = 8.3 Hz), 6.85 (d, 1H, J = 8.3 Hz), 5.95 (m, 1H) 3.86 (br s, 2H), 2.43-2.39 (m, 2H), 1.99-1.97 (m, 2H), 1.51 (t, 2H, J = 6.4 Hz) ), 0.99 (s, 6H).

c) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [6-bromo-2- (4,4-dimethyl-cyclohex-1-enyl) -pyridine- 3-yl] -amide

The title compound was prepared from 6-bromo-2- (4,4-dimethyl-cyclohex-1-enyl) -pyridin-3-ylamine (60 mg, 0.21 mmol as prepared above). , Potassium 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (91.0 mg, 0.290 mmol, as prepared in step (d) of Example 1) , PyBroP (157 mg, 0.330 mmol) and DIEA (91.0 μL, 0.520 mmol) were used following the procedure shown in step (f) of Example 1 (84 mg, 78%). ¹ H-NMR (CDCl ₃ ; 400 MHz): δ 9.91 (s, 1H), 8.64 (d, 1H, J = 8.6 Hz), 7.79 (s, 1H), 7.38 (d 1H, J = 8.6 Hz), 6.00 (m, 1H), 5.92 (s, 2H), 3.67 (m, 2H), 2.46 (m, 2H), 2.14 ( m, 2H), 1.62 (t, 2H, J = 6.3 Hz), 1.12 (s, 6H), 0.98 (m, 2H).

d) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [2- (4,4-dimethyl-cyclohex-1-enyl) -6- (1-ethoxy -Vinyl) -pyridin-3-yl] -amide

In a round bottom flask was added 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [6-bromo-2- (4,4-dimethyl-cyclohex-1-enyl)- Pyridin-3-yl] -amide (32 mg, 0.060 mmol as prepared above), Pd (PPh ₃ ) ₄ (7 mg, 0.006 mmol) and tributyl- (1-ethoxy- Vinyl) -stannane (30 mg, 0.080 mmol) was added and DMF (0.7 mL) was added thereto, and the resulting solution was stirred at 100 ° C. overnight. The reaction was diluted with EtOAc (25 mL), washed with water (2 × 25 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by preparative TLC (20% EtOAc-hexane) to give 12 mg (43%) of the title compound as an oil. Mass spectrum (ESI, m / z): Calculated as follows: C ₂₈ H ₃₉ N ₅ O ₃ Si, 522.2 (M + H), measured value: 522.3.

b) 5-Cyano-1H-imidazole-2-carboxylic acid [6-acetyl-2- (4,4-dimethyl-cyclohex-1-enyl) -pyridin-3-yl] -amide

The title compound was prepared from 5-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid [2- (4,4-dimethyl-cyclohex-1-enyl) -6- (1-Ethoxy-vinyl) -pyridin-3-yl] -amide (12 mg, 0.023 mmol as prepared above)) was added to 10 mL DCM, 0.4 mL EtOH and 10 mL TFA. The mixture was carried out through stirring for 1 hour at room temperature. The mixture was concentrated and triturated with Et ₂ O (4.4 mg, 52%). Mass spectrum (ESI, m / z): Value calculated as follows: C ₂₀ H ₂₁ N ₅ O ₂ , 364.1 (M + H), measured value: 364.1.

c) 4-Cyano-1H-imidazole-2-carboxylic acid [2- (4,4-dimethyl-cyclohex-1-enyl) -6- (2-methyl-oxazolidine-2-yl) -pyridin-3-yl ] -Amide The title compound was prepared from 5-cyano-1H-imidazole-2-carboxylic acid [6-acetyl-2- (4,4-dimethyl-cyclohex-1-enyl) -pyridin-3-yl] -amide This is carried out by following the procedure shown in step (h) of Example 1 using 2-aminoethanol (as prepared above).

  The following examples are prepared by following the procedures of the above examples using the corresponding reactants as shown in the table below:

IV. result
Fluorescence Polarization Competitive Immunoassay An autophosphorylated fluorescence polarization competitive immunoassay was used for the purpose of measuring the c-fms inhibitory ability exhibited by selected compounds of formula I. This assay was performed using black 96-well microplates (LJL BioSystems). The assay buffer used was 100 mM 4- (2-hydroxyethyl) piperazine 1-ethanesulfonic acid (HEPES) (pH 7.5), 1 mM 1,4-dithio-DL-threitol (DTT), 0. 01% (volume / volume) Tween-20. Immediately prior to performing the assay, the compound was diluted with assay buffer containing 4% dimethyl sulfoxide (DMSO). After 5 μL of the compound was added to each well, 3 μL of a mixture formed by adding 33 nM c-fms (Johnson & Johnson PRD) and 16.7 mM MgCl ₂ (Sigma) to the assay buffer was added. The kinase reaction was initiated by adding 2 μL of 5 mM ATP (Sigma) in assay buffer. The final concentration in the assay was 10 nM c-fms, 1 mM ATP, 5 mM MgCl ₂ , 2% DMSO. A control reaction was performed for each plate, with positive and negative control wells using assay buffer (made up to 4% in DMSO) instead of the compound in the positive and negative control wells. 1.2 μL of 50 mM ethylenediaminetetraacetic acid (EDTA) was added.

The plate was incubated for 45 minutes at room temperature. At the end of the incubation, the reaction was quenched with 1.2 μL of 50 mM EDTA (no EDTA was added to the positive control well at this point, see above). After incubation for 5 minutes, 10 μL of a 1: 1: 3 mixture of anti-phosphotyrosine antibody (10X), PTK green tracer (10X, vortex) and FP dilution buffer was placed in each well (all Pan Vera). From catalog number P2837). After the plate was covered and incubated at room temperature for 30 minutes, the fluorescence polarization was read with Analyst. The instrument settings were: 485 nm excitation filter; 530 nm emission filter; Z height: center of hole; G factor: 0.93. The fluorescence polarization values exhibited by the positive and negative controls under such conditions were about 300 and 150, respectively, and were used to define 100% and 0% inhibition of the c-fms response. The reported IC ₅₀ value is the average of three independent measurements.

Through CSF-1 induced bone marrow derived macrophage assay FCS 10% and recombinant mouse CSF-1 supplemented with 50 ng / ml alpha-MEM in a bacteriological dish and culturing mouse bone marrow therein Obtain macrophages. On day 6, macrophages are detached from the dish, washed, and then resuspended in alpha-MEM with 10% FCS content to a cell count of 0.05 million per ml. Distribute the cell suspension to a 96-well culture plate at 100 ul per well. The wells are further supplemented by adding 50 ul of medium containing 15 ng / ml of CSF-1, 3 uM of indomethacin and a 3X dilution of the test compound. The cells are cultured at 37 degrees for 30 hours under 5% CO2. During the last 6 hours, the culture is supplemented with an additional 30 ul of media containing a 1: 500 dilution of bromodeoxyuridine (BrDU). At the end of this incubation period, the plate is spun at 1000 RPM for 1 minute, and then 130 ul of medium is removed with a pipette and 150 ul of fixing solution is placed in place for 1 hour at room temperature. Next, the fixing agent is removed from the plate, and then the plate is dried with air. BrDU incorporated into the fixed and dried cells is quantified by specific ELISA.

  Table 2 shows the test results of the representative compounds of the present invention.

  While the foregoing specification has taught, by way of example, the principles of the invention for purposes of illustration, the practice of the invention is not limited to such variations as fall within the scope of the claims and their equivalents. It will be understood to encompass all applications and / or modifications.

  All publications disclosed in the above specification are fully incorporated herein by reference.

Claims (20)

Formula I

[Where:
W is

And each R ⁴ is independently H, F, Cl, Br, I, OH, OCH ₃ , OCH ₂ CH ₃ , SC _(1-4) alkyl, SOC _(1-4) alkyl, SO ₂ C _(1-4) alkyl, —C _(1-3) alkyl, CO ₂ R ^d , CONR ^e R ^f , C≡CR ^g or CN; and R ^d is H or —C _{(1-3 A)} alkyl;
R ^e is H or —C _(1-3) alkyl;
R ^f is H or —C _(1-3) alkyl; and R ^g is H, —CH ₂ OH or —CH ₂ CH ₂ OH;
R ² is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl, spiro-substituted piperidinyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, all of which are independently: Optionally substituted with one or two of each of fluoro, hydroxy, C _(1-3) alkyl and C _(1-4) alkyl;
Z is H, F or CH ₃ ;
J is CH or N;
X is

Is;
R ⁵ is, _{H, -C (1-6) alkyl, -OC (1-4) ^{alkyl, -CN, -NA 3 A 4,}} -SO 2 CH 3, -CO 2 C (1-4) alkyl, _{^{-CH 2 -NA 3 A 4, -CH}} 2 CH 2 NA 3 A 4, -CONA 3 A 4, -CH 2 OC (1-4) _{alkyl, -OC (1-4)} alkyl ^OR a, -NHCH ₂ CH ₂ CO ₂ C _{(1-4) alkyl, -NHCH 2 CH 2 OC (1-4} ) alkyl, _{-N (C (1-4) ^{alkyl) CH 2 CH 2 NA 3 A}} 4,
-OC _(1-4) alkyl _{^{NA 3 A 4, -OCH 2 CO}} 2 C (1-4) _{alkyl, -CH 2 CO 2 C (1-4} ) _{alkyl, -CH 2 CH 2 SO 2 C} (1- _{4) ^{alkyl, -SO 2 CH 2 CH 2 NA}} 3 A 4, -SOCH 2 CH 2 NA 3 A 4, -SCH 2 CH 2 NA 3 A 4, -NHSO 2 CH 2 CH 2 NA 3 A 4, phenyl, Imidazolyl, thiazolyl, 4H- [1,2,4] oxadiazol-5-onyl, 4H-pyrrolo [2,3-b] pyrazinyl, pyridinyl, [1,3,4] oxadiazolyl, 4H- [1,2 , 4] triazolyl, tetrazolyl, pyrazolyl, [1,3,5] triazinyl or [1,3,4] thiadiazolyl;
A ³ is —C _(1-4) alkyl or CH ₂ CH ₂ OR ^a ;
A ⁴ _{is, -C (1-4) ^{alkyl, COR a, CH 2 CON (}} CH 3) 2, -CH 2 CH 2 OR a, -CH 2 CH 2 SC (1-4) alkyl, _-CH 2 CH ₂ SOC _(1-4) alkyl or —CH ₂ CH ₂ SO ₂ C _(1-4) alkyl; or A ³ and A ⁴ together to form:

A nitrogen-containing heterocyclic ring selected from: and R ^a is H or C _(1-4) alkyl;
R ^aa is H or C _(1-4) alkyl; and R ^bb is H, —C _(1-4) alkyl, —CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ , —CH ₂ CO ₂ H _{, -C (O) C (1-4} ) alkyl or _{CH 2 C (O) C (} 1-4) alkyl]
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. W is

Is;
R ² is

Is;
X is

Is;
R ⁵ is H, —C _(1-6) alkyl, phenyl, —CH ₂ CH ₂ NA ³ A ⁴ , —CH ₂ CH ₂ SO ₂ CH ₃ , pyridyl, imidazolyl, —CH ₂ NA ³ A ⁴ or —CH ₂ OR ^a ; and A ³ is —CH ₃ ;
A ⁴ is —COCH ₃ or —CH ₃ ; or A ³ and A ⁴ together are

May form a nitrogen-containing heterocyclic ring selected from:
R ^a is H or —C _(1-4) alkyl;
R ^bb is —C _(1-4) alkyl or —COCH ₃ ;
A solvate, hydrate, tautomer and pharmaceutically acceptable salt thereof as well as the compound of claim 1. R ² is

Is;
X is

Is;
R ⁵ is —C _(1-3) alkyl, —CH ₂ NA ³ A ⁴ or —CH ₂ OR ^a ; and A ³ is —CH ₃ ;
A ⁴ is —COCH ₃ or —CH ₃ ; or A ³ and A ⁴ together are:

May form a nitrogen-containing heterocyclic ring selected from:
R ^a is H or —C _(1-4) alkyl;
R ^bb is —C _(1-4) alkyl or —COCH ₃ ;
A solvate, hydrate, tautomer and pharmaceutically acceptable salt thereof as well as the compound of claim 2. W is

Is;
R ² is

Is;
X is

Is
4. The solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof as well as the compounds of claim 3. W is

Is;
R ² is

Is;
X is

Is
5. The solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof as well as the compounds of claim 4. Formula I

[Where:
W is

Is;
R ² is

Is;
Z is H;
J is CH or N;
X is

Is;
R ⁵ is —C _(1-3) alkyl, —CH ₂ NA ³ A ⁴ or —CH ₂ OR ^a ; and A ³ is —CH ₃ ;
A ⁴ is either a -COCH ₃ or -CH _3; or ^{A 3} and ^{A 4} together below:

May form a nitrogen-containing heterocyclic ring selected from:
R ^a is H or —C _(1-4) alkyl;
R ^bb is —C _(1-4) alkyl or —COCH ₃ ]
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. following:

And a compound selected from the group consisting of solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.   A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.   A pharmaceutical dosage form comprising from about 0.5 mg to about 10 g of a pharmaceutically acceptable carrier and at least one compound of claim 1.   10. A dosage form according to claim 9 suitable for parenteral or oral administration.   A method of inhibiting the activity of a protein tyrosine kinase comprising contacting said kinase with an effective inhibitory amount of at least one compound according to claim 1.   The method according to claim 11, wherein the protein tyrosine kinase is c-fms.   A method of treating inflammation in a mammal comprising administering to said mammal at least one compound of claim 1 in a therapeutically effective amount.   A method of treating cancer in a mammal comprising administering to said mammal at least one compound of claim 1 in a therapeutically effective amount.   A method of treating a cardiovascular disease in a mammal comprising administering to said mammal at least one compound of claim 1 in a therapeutically effective amount.   Glomerulonephritis in mammals, inflammatory bowel disease, prosthetic organ failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor-related angiogenesis, age-related A method of treating a disease with an inflammatory component, including macular degeneration, diabetic retinopathy, restenosis, schizophrenia or Alzheimer's dementia, wherein the mammal has at least one species according to claim 1. Administering a compound in a therapeutically effective amount.   A method of treating skeletal pain or viscera caused by tumor metastasis or osteoarthritis in a mammal, including pain including inflammation and neurogenic pain, wherein said mammal in need of said treatment Administering a therapeutically effective amount of at least one compound.   Osteoporosis, Paget's disease and other illnesses where bone resorption mediates morbidity [rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthetic failure, osteolytic sarcoma, myeloma and bone 2. A method of treating a mammal comprising a tumor metastasis comprising administering a therapeutically effective amount of at least one compound of claim 1 to a mammal in need thereof.   A method for treating and preventing metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer and hairy cell leukemia, wherein said mammal is in need of said treatment. Administering a therapeutically effective amount of at least one compound.   A method of treating autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis or uveitis, to a mammal in need of said treatment 2. A method comprising administering at least one compound of claim 1 in a therapeutically effective amount.